Identifying regions of maximal linkage disequilbrium between a disease phenotype and a particular marker allele is a valuable means to pinpoint the chromosomal location of the responsible gene. Indeed, most of the efforts to positionally clone human disease genes have relied on the measurement of linkage disequilbrium. Markers on chromosomes 4 and 21 will be used to carry out linkage disequilibrium analysis of the Pima genome. These chromosomes were chosen for this study because they have been extensively mapped genetically and physically, and gene poor and gene rich regions have been identified and correlated to sequence composition over extensive lengths of chromosome 21. We have identified four additional chromosomal regions as possible linkage disequilibrium candidates because they show a high degree of genetic homogeneity in the Pima population. Increased homozygosity at these four microsatellite marker loci was found in the Pima genome following a random screen with 100 markers. Linkage disequilibrium analyses will be carried out using closely spaced markers in these regions as well. The statistical analyses of the typing data will be carried out by our collaborator. We are investigating the possibility that these regions of homogeneity might be associated with disease susceptibility in this population with a high prevalence of obesity and diabetes mellitus.